Belzutifan/Lenvatinib Bests Cabozantinib in PFS, ORR in ccRCC

The HIF-2α inhibitor belzutifan (Welireg) and lenvatinib (Lenvima) demonstrated superior progression-free survival (PFS) and objective response rate (ORR) vs cabozantinib (Cabometyx) in patients with advanced clear cell renal cell carcinoma (ccRCC) following immune checkpoint inhibitor therapy, according to results of the LITESPARK-011 trial (NCT04586231). Data from the first interim analysis (cutoff date, June 26, 2024) and second interim analysis (cutoff date, April 9, 2025) were presented, but Robert J. Motzer, MD, focused on the second interim analysis during his presentation at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium.¹

The median PFS was 14.8 months in the belzutifan/lenvatinib arm vs 10.7 months in the cabozantinib arm (HR, 0.70; 95% CI, 0.59-0.84; P = .00007).

“For both of these analyses, there was statistically superior benefit in [PFS] for belzutifan plus lenvatinib compared with cabozantinib,” said Motzer, the Jack and Dorothy Byrne Chair in Clinical Oncology and section head of kidney cancer at Memorial Sloan Kettering Cancer Center in New York, New York. “ORR was only studied at the first interim analysis and showed a statistically higher rate of ORR for the combination as well.”

At 24 months, patients in the treatment arm had an OS of 62.8% vs 55.4% in the control arm. The median OS in the belzutifan/lenvatinib arm was 34.9 months (95% CI, 27.5-not reached) vs 27.6 months (95% CI, 24.0-31.4) with an HR of 0.85 (95% CI, 0.68-1.05; P =.06075), which was not statistically significant. “This will be studied in the final OS analysis,” Motzer said.

ORR was 52.6% (95% CI, 47.3-57.7) for belzutifan/lenvatinib compared with 40.2% (95% CI, 35.2-45.3) for cabozantinib. “Note that there were 20 complete responses in the belzutifan/lenvatinib arm compared with only 4 in the cabozantinib arm,” Motzer said.

Duration of response (DOR) also favored the treatment arm. At 24 months, DOR was 49.5% in the belzutifan/lenvatinib arm vs 25.5% in the cabozantinib arm. Median DOR was 23.0 months for belzutifan/lenvatinib vs 12.3 months for cabozantinib. “To me, these are some of the most striking aspects of the results of this trial,” Motzer said.

Study Design

LITESPARK-011 evaluated patients with locally advanced or metastatic ccRCC who had progressed while receiving an immune checkpoint inhibitor as first- or second-line therapy. A total of 747 patients were randomly assigned to 120 mg of belzutifan and 20 mg of lenvatinib (n = 371) or 60 mg of cabozantinib (n = 376). Dual primary end points were PFS and OS, and secondary end points were ORR and DOR.

Investigators sought to determine the potential of combining a first-in-class HIF inhibitor with a VEGF-TKI (tyrosine kinase inhibitor). Because belzutifan is already approved² for advanced disease following both immunotherapy and VEGF-TKI treatment, the trial provides critical data on moving this combination into earlier lines of therapy for patients whose disease has progressed on checkpoint inhibition.

Patients were on belzutifan/lenvatinib longer than cabozantinib, with the median duration of therapy of 16.8 months vs 13.2 months, respectively. Nearly all patients in both arms experienced adverse events (AEs), and the number of patients who experienced a grade 3 or higher AE was nearly identical. There were 2 deaths reported in the belzutifan/lenvatinib arm and 1 death in the cabozantinib arm.

Baseline characteristics were balanced between the arms and were typical of a patient population with RCC.

Safety and Toxicity

The most common treatment-emergent AEs (TEAEs) reflect those associated with the individual agents. The most common TEAEs in the combination arm were anemia (69.2%), diarrhea (52.7%), and hypertension (58.8%). In the control arm, the most common TEAEs were diarrhea (70.1%), hypertension (56.6%), and skin toxicity (51.2%).

Time to worsening in disease-specific symptoms and quality of life were similar between belzutifan/lenvatinib vs cabozantinib.

“Belzutifan plus lenvatinib addresses an unmet clinical need and represents a potential new treatment option for patients with RCC that has progressed after anti–PD-L1 therapy,” Motzer concluded.

DISCLOSURES: Motzer has served in a consulting or advisory role to Merck. He has received research funding from Aveo (Inst), Bristol Myers Squibb (Inst), Eisai (Inst), Exelixis (Inst), Merck (Inst), and Pfizer (Inst).

REFERENCES

1. Motzer RJ, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti-PD-(L)1 therapy: open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7):417. doi:10.1200/JCO.2026.44.7_supplLBA417

2. FDA approves belzutifan for advanced renal cell carcinoma. News release. FDA. December 14, 2023. Accessed February 28, 2026. https://tinyurl.com/mtxm3fju